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Recent experimental data show that some human genetic diseases are due to mutations in proteins which influence their trafficking and lead to retaining of proteins in the endoplasmic reticulum or their unproper processing. In this paper a hypothesis is proposed that these mutations are connected with an incomplete protein folding, blocking it at the stage of the kinetic molten globule or even earlier. If so, the specific drugs against these diseases may be ligands and other factors which facilitate the correct protein folding.

A hypothesis is proposed explaining the mechanism of pH-induced release of retinol from retinol-binding protein (RBP). A number of conservative positively charged side chains located on the retinol-binding face of the RBP molecule are involved in salt bridges with conservative negatively charged groups. At low pH these salt bridges are broken and the retinol-binding face of RBP holds from 8 to 12 positively charged groups, which can ensure a proper orientation of the RBP molecule relative to a negatively charged membrane, facilitating the release of retinol. The disruption of salt bridges and the electrostatic repulsion of positive charges can soften the structure of the molecule near the entrance to the retinol-binding pocket, which can trigger both the release of retinol and the transition of RBP to the molten globule state.

The guanidine hydrochloride-induced unfolding of human alpha-lactalbumin has been studied by isothermal calorimetry. It has been shown that a cooperative transition takes place only in the concentration interval of the denaturant between 0.3 and 2 mol X l-1. The cooperative transition coincides with the transition detected by circular dichroism in the near-ultraviolet region which reflects the destruction of the specific environment of aromatic side groups. According to scanning calorimetric investigations, the transition disappears in the acid form of the protein where circular dichroism of aromatic side groups is practically absent. At higher concentrations of guanidine hydrochloride, where destruction of the secondary structure and unfolding of the chain are observed, there is no cooperative heat absorption.

Strong evidence exists that the translocation of proteins across a variety of membranes involves a non-native or denatured conformational states. On the other hand a compact state having secondary but not rigid tertiary structure and called the 'molten globule' state has been identified as being stable under mild denaturing conditions. A similar state has been shown to accumulate on the folding pathway of globular proteins. These states are compact though sufficiently expanded to include water, and they are internally mobile. It is proposed that these molten globule states may be suitable candidates for protein translocation across biological membranes.